Experimental approach may reverse rheumatoid arthritis and os...( Researchers have identified a mechan...),Health

Researchers have identified a mechanism that may keep a well known signaling molecule from eroding bone and inflaming joints, according to an early study published online today in the Journal of Clinical Investigation.

Bone is continually recycled to maintain its strength through the competing action of osteoclasts, cells that break down aging bone, and osteoblasts, which build new bone. Osteoclasts also play a central role in common diseases that erode bone, where two signaling molecules, TNFα and RANKL, cause too much bone breakdown. Both are known to turn on the nuclear factor kappa B complex (NF-κB), which turns on genes that cause the stem cell precursors of osteoclasts to mature and start eating bone. While both TNFα and RANKL encourage bone loss, the current study argues that TNFα and RANKL have different effects on levels of a key inhibitory protein within the NF-κB pathway called NF-κB p100, with important consequences for drug design.

The NF-κB pathway as a whole signals for more active osteoclasts, but NF-κB p100 (p100) interferes with the ability of that same pathway to pass on the bone loss signal. While both TNFα and RANKL activate NF-κB signaling, RANKL efficiently converts p100 into a form that no longer blocks NF-κB pathway signaling and that leads to bone loss. In contrast, the current study is the first to show that TNFα lets p100 build up. Thus, TNFα both causes bone loss through NF-κB signaling and limits it via p100 accumulation.

Experiments found further that mice genetically engineered to lack NF-κB2p100 suffered more severe joint erosion and inflammation than their normal littermates in the face of TNFα. TNFα, but not RANKL, also increased levels of a protein in osteoclast precursors called TNF receptor-associated factor 3 (TRAF 3), which may help NF-κB p100 block osteoclast formation and inflammation.

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